Our objective is to understand the mechanisms by which cell-cell contact-mediated signaling in polarized epithelial cells regulates epithelial architecture and oncogenesis. E-cadherin is a cell-cell adhesion molecule that is essential to development and function of polarized epithelial organs. Strikingly, E-cadherin is also a major tumor suppressor. Loss of E-cadherin expression occurs in familial cancer syndromes and sporadic cancer, with renal cell carcinoma serving a prominent example of both. The tumor suppressive role of E-cadherin has previously been ascribed to inhibition of cell motility and effects on Wnt signaling. Here we seek to define a novel tumor suppressor function for E- cadherin. We have determined that anoikis (homelessness), which denotes apoptosis elicited by deprivation of cell-matrix interaction, is mediated by cadherin-engagement. Resistance to anoikis is a hallmark of metastatic capacity. We have established that ?PIX, an activator of the Cdc42 and Rac GTPases, confers protection against cadherin- mediated apoptosis in kidney epithelial cells. ?PIX binds directly to Scrib, a tumor suppressor that promotes E-cadherin-mediated cell-cell adhesion. This proposal tests the hypothesis that the ?PIX-Scrib complex modulates cadherin-mediated survival signaling in epithelial cells. It moreover addresses the putative pro-apoptotic function of E-cadherin in the context of clear cell renal cell carcinoma (CC-RCC). The von Hippel- Lindau tumor suppressor gene VHL, a regulator of E-cadherin expression, plays a major causal role in CC-RCC. The goals of this proposal will be accomplished in three aims. Aim 1 establishes the requirement for functional domains in ?PIX to counteract cadherin- mediated apoptosis. Aim 2 defines the role of the Scrib-?PIX complex in apoptosis elicited by cadherin-engagement. Aim 3 determines whether loss of VHL in CC-RCC confers protection against E-cadherin-mediated apoptosis. Collectively, the proposed studies will elucidate a novel function of E-cadherin of pivotal importance to epithelial morphogenesis and tumor suppression. PUBLIC HEALTH RELEVANCE: Epithelial cell-cell adhesion is essential to development and function of internal organs, as well as in prevention of tumor formation by mechanisms that are not well understood. We have discovered that epithelial cell-cell adhesion regulates programmed cell death, and have identified components of the machinery that prevents this death in normal epithelial cells. Elucidation of these mechanisms is important to our understanding of epithelial cancers, which account for more that 80% of all cancer fatalities.